title: Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment.
abstract: The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting κ-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Kuzmin
authors.forename: V
authors.initials: V
authors.lastname: Chefer
authors.forename: I
authors.initials: I
authors.lastname: Bazov
authors.forename: J
authors.initials: J
authors.lastname: Meis
authors.forename: S O
authors.initials: SO
authors.lastname: Ögren
authors.forename: T
authors.initials: T
authors.lastname: Shippenberg
authors.forename: G
authors.initials: G
authors.lastname: Bakalkin
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004399:Dynorphins / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007858:Learning / Q000187:drug effects / Q000502:physiology; D018782:Maze Learning; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D017551:Microdialysis; D009271:Naltrexone / Q000031:analogs & derivatives; D009292:Narcotic Antagonists; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D000431:Ethanol; D018698:Glutamic Acid; D009271:Naltrexone; D004399:Dynorphins